Methods of preventing breast cancer

ABSTRACT

A method of preventing breast cancer comprising administering for a sufficient term to a human in need thereof an effective amount of a compound having the formula  
                 
 
     and pharmaceutically acceptable salts and solvates thereof.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/029,850, filed Oct. 30, 1996, and U.S. ProvisionalApplication No. 60/040,260, filed Mar. 10, 1997.

BACKGROUND OF THE INVENTION

[0002] Breast carcinoma or cancer is a major medical problem for womenbeginning in the third decade of life and continuing throughoutsenescence. It is currently estimated that in the United States womenhave a one in eight chance of developing the disease in their lifetime(by the age of eighty), whereas one in twenty-eight women have alifetime risk of dying from breast cancer (Harris et.al., Ed. Diseasesof the Breast, 1996: pp. 159-168). Carcinoma of the breast is the thirdmost common cancer, and the most common cancer in women. It is a majorcause of mortality in women, as well as a cause of disability,psychological trauma, and economic loss. Breast carcinoma is the secondmost common cause of cancer death in women in the United States, and forwomen between the ages of 15 and 54, the leading cause of cancer-relateddeath (Forbes, Seminars in Oncology, vol.24(l), Suppl 1, 1997:pp.S1-20-S1-35). Indirect effects of the disease also contribute to themortality from breast cancer including consequences of advanced disease,such as metastases to the bone or brain. Complications arising from bonemarrow suppression, radiation fibrosis and neutropenic sepsis,collateral effects from therapeutic interventions, such as surgery,radiation, chemotherapy, or bone marrow transplantation-also contributeto the morbidity and mortality from this disease.

[0003] The epidemiology of this disease, although the subject of intenseinvestigation, is still poorly understood. There appears to be asubstantial genetic component which predisposes some women to contractthe disease. Yet it is not clear whether this genetic component iscausative or permissive to the disease, or only predictive of thedisease process. Although it has been known for a long time that breastcarcinoma tends to occur more frequently in some families, such analysisis not always predictive of disease occurrence in other family membersand is of little value for prediction of its prevalence in the generalpopulation. It is currently estimated that only 5% of all breast cancersresult from a genetic predisposition (Harris et.al., Ed. Disease of theBreast, 1996: pp.159-168).

[0004] Extensive clinical and pharmacological investigation has beenconducted in the attempt to elucidate the relationship between thehormone estrogen, and the cause and maintenance of breast carcinoma.Risk factors for the disease are principally related to the duration ofa woman's cumulative estrogen exposure and include: age at menarche,parity, age at the time of the first full-term pregnancy, and menopause.Although much is known about the relationship of estrogen in themaintenance of the disease and the importance of estrogen dependencewith respect to endocrine treatment of the disease, there isconsiderable controversy over the role of estrogen in the pathogenesisof this disease, i.e., whether estrogen is a causative agent(initiator), or an obligatory co-factor (promotor) in the process ofcarcinogenesis.

[0005] Estrogen, which includes 17-β-estradiol, estrone, and theiractive metabolites, is a major sex-related hormone in women, butadditionally, it appears to be an important homeostatic hormone in bothmen and women throughout their adult life. All humans have some level ofendogenous estrogen. Yet the vast majority of people do not developbreast carcinoma, supporting a position that estrogen, per se, is not aninitiator of carcinogenesis, such as is the case with a chemical orenvironmental carcinogen. Additionally, women, as they go throughmenopause with the consequent loss of endogenous ovarian estrogenproduction, do not experience a commensurate reduction in their risk ofcontracting this disease. In fact, apart from a personal history ofbreast cancer, age is the single greatest risk factor for developingthis disease. Breast cancer is rare in women younger than age 20, butthis risk increases rapidly with age. When compared with a 20-year-oldwoman's risk of developing breast cancer, a woman age 40 to 49 has a40-fold increase in risk, a woman age 50 to 59 a 60-fold increase, and awoman over the age of 60 has a risk 90-fold higher than that of heryounger counterpart (Forbes, Seminars in Oncology, vol.24(1), Suppl 1,1997: pp.S1-20-S1-35).

[0006] Hormone replacement therapy (HRT) is often recommended forpostmenopausal and peri-menopausal women to alleviate menopausalsymptoms and reduce the risk of cardiovascular disease, osteoporosis,and other serious sequellae of long-term estrogen deficiency. However,because of well-accepted data on the direct effects of cumulativelifetime estrogen exposure and breast cancer risk, there is vigorousdebate over the potential of hormone replacement to increase a woman'srisk of developing breast carcinoma. While short-term HRT (less than 5years) is associated with minimal or no increase in risk, epidemiologicstudies and meta-analyses of long-term HRT use (between five and sevenyears) report increases in the risk of developing breast cancer of 35%to 75% (Grady et.al., Hormone Therapy to Prevent Disease and ProlongLife in Postmenopausal Women., Ann Intern Med, 117: pp.1016-1037, 1992).

[0007] Theories and evidence regarding the role of estrogen in thepathogenesis of this disease are complex. Experimental models of mammarycarcinoma in rats require administration of a carcinogen for tumorinduction (tumorigenesis), whereas estrogen behaves as a promoter(rather than an initiator) of this process. Ovariectomy, in these animalmodels, will interfere with this process of chemically-inducedcarcinogenesis. In humans, however, the timing of the carcinogenic eventis unknown. What is known is that women who undergo premature menopauseor medical or surgical oophorectomy before the age of 40, will have anapproximately 50% reduction in breast cancer risk compared with womenundergoing natural menopause at age 50 (Harris, et.al., Ed. Diseases ofthe Breast, 1996: pp.159-168). It is logical, therefore, that approachesfor the prevention of breast cancer would target the reduction inlifetime estrogen exposure. This can be accomplished bypharmacologically-induced estrogen deprivation, through theadministration of an agent which would block the production and/oraction of estrogen anywhere along the hypothalamic-pituitary-gonadalaxis. It is nevertheless problematic to extrapolate the probable successof preventing breast carcinoma, de novo or otherwise, with agents ofthis nature.

[0008] In contrast to the complex role of estrogen in the pathogenesisof this disease, and despite a continually evolving body of data,considerable advances have been made in our understanding of the effectsof estrogen in the setting of established breast carcinoma. Estrogen isa growth factor to most breast carcinoma cells in the early stages ofthe disease. The rapidly dividing cells are sensitive to its effectsthrough the estrogen receptor. It has also been established, althoughnot well understood that, at some point during the course of thisdisease process, transformed (cancer) cells often lose their sensitivityto the promoting effects of estrogen. Eventually, a majority ofcarcinoma cells become independent of estrogen for growth and lose theirresponsiveness to hormonally based therapy, which broadly includes: theGNRH agonists, “anti-estrogens,” progestins, and androgens.

[0009] Enormous benefit in the treatment of breast cancer has beenachieved with the advent and widespread use of hormonally basedtherapeutic interventions. The most extensively used endocrine therapyis tamoxifen. The five-year survival rate for women with breastcarcinoma has been dramatically improved with this therapy; however, noadditional benefit or survival advantage is achieved by continuingtherapy for more than five years. In fact, data indicate a decrease indisease-free survival as well as overall survival, with greater thanfive years tamoxifen use (NSABP B-14 Trial; Fisher et al. Five VersusMore Than Five Years of Tamoxifen Therapy for Breast Cancer PatientsWith Negative Lymph Nodes and Estrogen Receptor-Positive Tumors, J NatlCanc Inst, vol.88)(21): pp.1529-1542, 1996). Unfortunately tamoxifen isalso associated with significant adverse effects such as: asignificantly increased incidence of venous thromboembolism,substantially increased incidence of vasomotor symptoms or hot flashes(in the range of 16-67%), cataract formation, and DNA-adduct formationwhich, although not clinically confirmed, still raises concerns aboutthe potential for hepatocellular carcinoma (observed experimentally inanimal models). The most serious event, however, is tamoxifen'sestrogenic effect in the uterus which causes endometrial hyperplasia anda substantial increase in the incidence of endometrial carcinomas (athree to four-fold increase in risk after five years tamoxifenadministration) (Goldhirsch et.al., Endocrine Therapies of BreastCancer, Sem in Onc, vol.23(4), pp.494-505, 1996). For this reason andthe lack of improvement in survival advantage with long-term tamoxifenuse, tamoxifen therapy of longer than five years is now contraindicated.

[0010] Data suggest that with long-term tamoxifen exposure, breast tumorcells undergo alterations that cause them to develop resistance to itsantiestrogenic effects, and alternatively respond to its estrogenicproperties (Santen, Editorial: Long Term Tamoxifen Therapy: Can anAntagonist become an Agonist?, J Clin Endo & Metab, vol. 81(6),pp.2027-2029, 1996). Changes in any step in the estrogen receptorsignaling pathway may be responsible for the mechanism of development ofresistance to tamoxifen therapy, some of which do not causecross-resistance to other hormonal therapies and some of which do resultin complete unresponsiveness to endocrine therapy of any kind. Onemechanism for tamoxifen resistance has been attributed to the gradualevolution of the carcinoma cells from estrogen dependence to estrogenindependence (estrogen receptor positive cells become estrogen receptornegative). Thus, even with the most advanced available combinations oftreatment modalities, (surgery, radiation, and/or chemotherapy), thelong-term prognosis for patients is poor, especially when metastaticdisease is present. Clearly, there is a great need for improvedtherapies and, perhaps most important, a critical need for theprevention of the disease in the first instance (de novo, or primaryprevention).

[0011] Although tamoxifen has been extensively studied and provenefficacious in the setting of established disease, there have been nocompleted, large-scale, prospective placebo-controlled, clinical trialsaddressing the potential use of this compound for primary prevention ofbreast cancer. Studies do exist indicating that women with a history ofcarcinoma in one breast and treated with tamoxifen, have a decreasedincidence of tumor occurrence in the contralateral breast. Although thiscould be interpreted as a type of prevention of the disease, it is notclear whether this is an anti-metastatic effect or a de novo inhibitionof the disease. Understanding such a distinction in biological mechanismis very important in attempting to prevent de novo disease initiation inhealthy women with no particular history or risk factor for breastcarcinoma.

[0012] For the last decade it has been argued that “anti-estrogen”therapy, especially the use of tamoxifen, should be studied for itspotential to prevent de novo breast carcinoma. However, partiallybecause of the lack of evidence of a benefit, and the known andpotential toxicities of tamoxifen, no prospective prevention trials havebeen conducted in healthy women. Recently, two such prevention trialshave been proposed and each trial has been the subject of substantialcontroversy. As a result, the trial to be done in the United Kingdom wasdeemed to have an unfavorable risk-to-benefit ratio and was notundertaken. Similarly in Italy, safety concerns regarding the occurrenceof endometrial cancers, mandated that tamoxifen prevention studies beconducted only in women who had undergone hysterectomies In the UnitedStates, however, such a trial was undertaken under the auspices of theNational Cancer Institute. In recognition of the controversial analysisof such trials, and the enormous sample size otherwise required, the UStrial is limited only to women who are at high risk of developing thedisease and includes both pre- and post-menopausal women (young womenmust have had a risk assessment equivalent to that of a 60-year-oldwoman for study eligibility). The results of this trial will not beavailable for at least three years. (For further information regardingthe arguments for the potential use of tamoxifen as a chemopreventiveagent in breast carcinoma, clinical design, and definition of high riskpotential; see: “Breast Cancer Prevention Study: Are Healthy Women Putat Risk by Federally Funded Research?”, Transcript of the Hearing Beforethe Human Resources and Intergovernmental Relations Subcommittee of theCommittee on Governmental Operations, House of Representatives of theOne Hundred Second Congress, Second Session, Oct. 22, 1992 [ISBN0-16-044316-4] and references and testimony cited therein).

[0013] Because the goal of disease prevention is to protect women fromthe carcinogenic event (or the occurrence of precancerous lesions) andthe subsequent promotion or progression to invasive disease (cancer),prolonged use of a preventive therapeutic agent is necessary (Kelloffet.al. Approaches to the Development and Marketing Approval of Drugsthat Prevent Cancer, Cancer Epidemiology, Biomarkers & Prevention, vol4, pp.1-10, 1995). This would require the therapy to be extremelywell-tolerated, with an exceptional safety profile and minimal sideeffects. Raloxifene has been studied in more than 12,000 subjects.Extensive integrated data from Phase III clinical trials of raloxifenefor the prevention or treatment of osteoporosis in postmenopausal women,has been analyzed for safety. When all doses of raloxifene areintegrated, this analysis has included more than 12,850 patient-years ofexposure to raloxifene. Raloxifene has been proven to be extremelywell-tolerated, to have a wide therapeutic index, and to have minimalevidence of acute or chronic toxicity, based on nearly 3 years ofclinical experience. The adverse effects associated with long-termtamoxifen use, in comparison, raise significant concerns over itssuitability for use as a chemopreventive agent (Grainger et.al.Tamoxifen: Teaching an Old Drug New Tricks, Nat Med, vol.2(4),pp.381-385, 1996).

[0014] To date, there is no demonstrated, effective prevention therapyfor de novo breast carcinoma. Further, there are no investigations inprogress or contemplated for preventing breast carcinoma in women in thegeneral population who are at no particular increased risk of developingbreast cancer. Clearly, a great need exists for a breast cancerprevention therapy useful for the entire population, includingindividuals at high risk, as well as individuals at no particularincreased risk, and including both men and women.

[0015] The current invention provides methods for the prevention ofbreast cancer, including de novo breast cancer.

SUMMARY OF THE INVENTION

[0016] The invention is directed to a method for preventing breastcancer in a human which comprises administering to said human for asufficient term an effective dose of a compound of the formula

[0017] or a pharmaceutically acceptable salt or solvate thereof.

[0018] Further, the invention relates to articles of manufacture whichcomprise packaging material and a pharmaceutical agent contained withinsaid packaging material, where the packaging material includes a labelwhich indicates the pharmaceutical agent may be administered forpreventing breast cancer, where the pharmaceutical agent is a compoundof formula I or a pharmaceutical acceptable salt or solvate thereof.

BRIEF DESCRIPTION OF THE DRAWING

[0019]FIG. 1 depicts the percentage incidence of breast cancer inplacebo and Raloxifene hydrochloride treated patients inplacebo-controlled studies.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The current invention concerns the discovery that compounds offormula I are useful for preventing breast cancer. The methods providedby this invention are practiced by administering to a human in needthereof a dose, for a sufficient term, of raloxifene or apharmaceutically acceptable salt or solvate thereof, that is effectiveto prevent breast cancer.

[0021] The term “prevent”, when used in conjunction with breast cancer,includes reducing the likelihood of a human incurring or developingbreast cancer. The term does not include treating a patient diagnosedwith breast cancer.

[0022] The term “de novo”, as used in the current invention, means thelack of transformation or metamorphosis of normal breast cells tocancerous or malignant cells in the first instance. Such atransformation may occur in stages in the same or daughter cells via anevolutionary process or may occur in a single, pivotal event. This denovo process is a process distinct from that of metastasis,colonization, or spreading of already transformed or malignant cellsfrom the primary tumor site to new locations. The term “de novo” isassociated with primary prevention. This invention also relates to theadministration of a compound of formula I to a patient who is atincreased risk of developing breast cancer, de novo or otherwise.

[0023] A person who is at no particular risk of developing breast canceris one who may develop de novo breast cancer, has no evidence orsuspicion of the potential of the disease above normal risk, and who hasnever had a diagnosis of having the disease. The greatest risk factorcontributing to the development of breast carcinoma is a personalhistory of breast cancer, even when there is no evidence of residualdisease, a person is 5 years or more beyond treatment for the disease,and the person is considered a “breast cancer survivor”. Anotherwell-accepted risk factor is family history of the disease.

[0024] Raloxifene, which is the hydrochloride salt of the compound offormula 1, has been shown to bind to the estrogen receptor and wasoriginally thought to be a molecule whose function and pharmacology wasthat of an “anti-estrogen”. Indeed, raloxifene does block the action ofestrogen in some tissues; however in others, raloxifene activates thesame genes as estrogen, displays similar pharmacology, and behaves as anestrogen agonist, for instance in the skeleton and on serum lipids. Theunique profile which raloxifene displays and differs from that ofestrogen, and other “anti-estrogens”, is now thought to be due to theunique activation and/or suppression of various gene functions by theraloxifene-estrogen receptor complex as opposed to the activation and/orsuppression of genes by the estrogen-estrogen receptor complex.Therefore, although raloxifene and estrogen utilize and compete for thesame receptor, the pharmacological outcome from gene regulation of thetwo is not easily predicted and is unique to each.

[0025] Generally, the compound is formulated with common excipients,diluents or carriers, and compressed into tablets, or formulated aselixirs or solutions for convenient oral administration, or administeredby the intramuscular or intravenous routes. The compounds can beadministered transdermally or intravaginaly, and may be formulated assustained release dosage forms, parenteral forms, depo forms, and thelike.

[0026] The compounds used in the methods of the current invention can bemade according to established procedures, such as those detailed in U.S.Pat. Nos. 4,133,814, 4,418,068, 4,380,635, 5,629,425, U.K. PatentApplication GB 2,293,602, published Mar. 3, 1996, European PatentApplication 95301291, filed Feb. 28, 1995, published Sep. 6, 1995, andPCT application PCT/US97/04259 having an international filing date ofMar. 20, 1997, and a publication date of circa Sep. 26, 1997 all ofwhich are incorporated by reference herein. In general, the processstarts with a benzo[b]thiophene having a 6-hydroxyl group and a2-(4-hydroxyphenyl) group. The hydroxyl groups of the starting compoundare protected, the three position is acylated, and the productdeprotected to form the formula I compounds. Examples of the preparationof such compounds are provided in the U.S. patents and UK application,discussed above.

[0027] The compounds used in the methods of this invention formpharmaceutically acceptable acid and base addition salts with a widevariety of organic and inorganic acids and bases and include thephysiologically acceptable salts which are often used in pharmaceuticalchemistry. Such salts are also part of this invention. Typical inorganicacids used to form such salts include hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.Salts derived from organic acids, such as aliphatic mono anddicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aroratic acids, aliphatic and aromaticsulfonic acids, may also be used. Such pharmaceutically acceptable saltsthus include acetate, phenylacetate, trifluoroacetate, acrylate,ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzene-sulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. A preferred salt is thehydrochloride salt.

[0028] The pharmaceutically acceptable acid addition salts are typicallyformed by reacting a compound of formula I with an equimolar or excessamount of acid. The reactants are generally combined in a mutual solventsuch as diethyl ether or benzene. The salt normally precipitates out ofsolution within about one hour to 10 days and can be isolated byfiltration or the solvent can be stripped off by conventional means.

[0029] Bases commonly used for formation of salts include ammoniumhydroxide and alkali and alkaline earth metal hydroxides, carbonates, aswell as aliphatic and primary, secondary and tertiary amines, aliphaticdiamines. Bases especially useful in the preparation of addition saltsinclude sodium hydroxide, potassium hydroxide, ammonium hydroxide,potassium carbonate, methylamine, diethylamine, ethylene diamine andcyclohexylamine.

[0030] The pharmaceutically acceptable salts generally have enhancedsolubility characteristics compared to the compound from which they arederived, and thus are often more amenable to formulation as liquids oremulsions.

[0031] Pharmaceutical formulations can be prepared by procedures knownin the art. For example, the compounds can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; moisturizing agents such as glycerol; disintegrating agentssuch as calcium carbonate and sodium bicarbonate; agents for retardingdissolution such as paraffin; resorption accelerators such as quaternaryammonium compounds; surface active agents such as cetyl alcohol,glycerol monostearate; adsorptive carriers such as kaolin and bentonite;and lubricants such as talc, calcium and magnesium stearate, and solidpolyethyl glycols.

[0032] The compounds can also be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for instance by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular part of the intestinaltract, possibly over a period of time. The coatings, envelopes, andprotective matrices may be made, for example, from polymeric substancesor waxes.

[0033] The particular effective and sufficient term and dosage of acompound of formula I required to prevent breast cancer, according tothis invention will depend upon the patient's physical characteristics,the route of administration, and related factors that will be evaluatedby the attending physician. A preferred term of administration is atleast six months, more preferred is at least one year, and mostpreferred is at least two years, or chronically. Generally, accepted andeffective daily doses will be from about 0.1 to about 1000 mg/day, andpreferably from about 30 to about 200 mg/day, and more preferably fromabout 50 to about 150 mg/day. A most preferred dosage range is betweenabout 60 and about 120 mg/day, with 60 mg/day particularly preferred.

[0034] The dosage ranges described are not meant to limit the invention.Rather, the ranges illuminate the invention, and the inventionencompasses those ranges which are functionally equivalent by providingthe discovered chemo-preventative characteristics of the compound.Therefore, while certain modes of administration may allow for aliterally different dosage range of the compound of formula I to be usedeffectively per the invention, such literally different dosage ranges,as it is functionally equivalent to the expressed ranges, areencompassed by the invention.

[0035] Further, the dosage ranges delineated are based on thehydrochloride salt of the compound of formula I. Therefore, the 60 mgdose is equivalent to 55.71 mg of the free base. One of ordinary skillin the art will be able to calculate the free base equivalent of anysalt of a compound of formula I which is pharmaceutically acceptable.For example, “about 60 mg” would encompass 55 to 65 mg of raloxifenehydrochloride, while encompassing 51.73 to 60.35 mg of the free base.

[0036] It is also advantageous to administer a compound by the oralroute. For such purposes the following oral dosage forms are available.

Formulations

[0037] Formulation 1: Gelatin Capsules Hard gelatin capsules areprepared using the following: Ingredient Quantity (mg/capsule)Raloxifene HCL  30-200 Starch, NF  0-650 Starch flowable powder  0-650Silicone fluid 350 centistokes  0-15

[0038] The ingredients are blended, passed through a No. 45 mesh U.S.sieve, and filled into hard gelatin capsules.

[0039] Examples of capsule formulations include those shown below:Ingredient Quantity (mg/capsule) Formulation 2: Raloxifene capsuleRaloxifene HCL  30-200 Starch, NF 112 Starch flowable powder 225.3Silicone fluid 350 centistokes 1.7 Formulation 3: Raloxifene capsuleRaloxifene HCL  30-200 Starch, NF 108 Starch flowable powder 225.3Silicone fluid 350 centistokes 1.7 Formulation 4: Raloxifene capsuleRaloxifene HCL  30-200 Starch, NF 103 Starch flowable powder 225.3Silicone fluid 350 centistokes 1.7 Formulation 5: Raloxifene capsuleRaloxifene HCL  30-200 Starch, NF 150 Starch flowable powder 397Silicone fluid 350 centistokeg 3.0

[0040] The specific formulations above may be changed in compliance withthe reasonable variations provided.

[0041] A tablet formulation is prepared using the ingredients below:Formulation 6: Tablets Ingredient Quantity (mg/tablet) Raloxifene HCL 30-200 Cellulose, microcrystalline  0-650 Silicon dioxide, fumed  0-650Steaxate acid  0-15

[0042] The components are blended and compressed to form tablets.

[0043] Alternatively, tablets each containing 0.1-1000 mg of activeingredient are made up as follows: Formulation 7: Tablets IngredientQuantity (mg/tablet) Raloxifene HCL  30-200 Starch 45 Cellulose,microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in water)Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc 1

[0044] The active ingredient, starch, and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

[0045] Suspensions each containing 0.1-1000 mg of medicament per 5 mLdose are made as follows: Formulation 8: Suspensions Ingredient Quantity(mg/5 ml) Raloxifene HCL 30-200 Sodium carboxyniethyl cellulose 50 mgSyrup 1.25 mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v.Purified water to 5 mL

[0046] The medicament is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

[0047] Preferred tablet formulations include the following two:Ingredient Quantity (mg) Function Formulation 9: Raloxifene HCL 60.0Active Spray Dried Lactose 30.0 Soluble Diluent Anhydrous Lactose 12.0Soluble Diluent Povidone 12.0 Binder Polysorbate 80 2.4 Wetting AgentCrospovidone 14.4 Disintegrant Magnesium Sterate 1.2 Lubricant (CoreTablet Weight 240.0) Film Coating Color Mixture White 12.0 ColoringAgent Talc trace Polishing Aid Carnauba Wax — Polishing Aid Formulation10: Raloxifene HCL 60.0 Active Spray Dried Lactose 29.4 Soluble DiluentAnhydrous Lactose 120.0 Soluble Diluent Povidone 12.0 Binder Polysorbate80 2.4 Wetting Agent Crospovidone 14.4 Disintegrant Magnesium Sterate1.2 Lubricant (Core Tablet Weight 240.0) Film Coating Color MixtureWhite 12.0 Coloring Agent Talc — Polishing Aid Carnauba Wax tracePolishing Aid

TEST PROCEDURE

[0048] As support for the utility of the current invention, the interimsafety results of Phase III clinical trials with raloxifene arepresented, below.

[0049] The majority of cases of breast carcinoma have occurred in thelarge, ongoing osteoporosis treatment study of 7704 postmenopausal womenwith established osteoporosis. However additional cases have beenreported in smaller studies of postmenopausal women at risk forosteoporosis. The studies reported herein are double-blind andplacebo-controlled; most have durations of approximately three years andwere designed to determine the efficacy of raloxifene to prevent ortreat osteoporosis in postmenopausal women. In addition, the studiesprovide information on the status of cardiovascular health and othermajor medical conditions (including the incidence of breast carcinoma).Patients were randomly assigned to receive either placebo, 30 mg, 60 mg,120 mg or 150 mg of drug per day, orally. All patients and investigatorsare blinded to study drug assignment (double-blind design). All patientsin all groups received daily calcium supplements of approximately 500mg/day. In addition, patients in the large, 7704-patient treatment studyreceived Vitamin D supplements, 400-600 IU/day.

[0050] Subjects selected for these studies are postmenopausal women (atleast 2 years from the time of the last menstrual period), ages rangefrom approximately forty-five to eighty years.

[0051] Typical exclusion criteria from participation in these studiesincluded: 1)the presence of serious systemic disease, 2)acute or chronicliver disease, 3)substantially impaired kidney function, 4)subjects who,in the opinion of the investigator, have poor medical or psychiatricrisk factors for inclusion in a clinical trial, e.g., drug or alcoholabuse, etc. 5)subjects with any history of cancer within five years ofentry into the study, with the exception of superficial lesions, e.g.,basal cell carcinoma of the skin 6)the presence of abnormal uterinebleeding. Most important of the exclusion criteria was the exclusion ofwomen with present or past personal history of breast cancer or otherestrogen-dependent neoplasia. These exclusion criteria generate apopulation of subjects which reflects the general population in regardto the risk of developing breast carcinoma, or in other words, thosepersons at no particular increased risk of developing breast cancer.

[0052] Potential subjects were screened prior to enrollment into thestudy. Subjects were required to reveal their medical histories andcurrent medical conditions. All potential patients were required eitherto have a baseline mammogram or ultrasound evaluation of the breast, orto have had one of these procedures in the 12-month period precedingstudy entry. In most studies, a two-year follow-up mammogram isrequired; however, annual mammograms are recommended. All subjects withdiagnosed and reported carcinomas of the breast were required todiscontinue immediately from study participation, and were referred bythe site investigator for appropriate oncologic evaluation and care.

[0053] For all placebo-controlled trials of at least 6 months durationand in all subjects receiving more than 1 month of treatment with astudy drug, a total of 42 breast cancer cases were reported: 24 caseswere observed in the placebo group compared with 18 in the raloxifenetreatment groups. The overall ratio of treatment assignments forrandomized patients (raloxifene to placebo) is approximately 2:1.

[0054] The results shown in Tables 1-4 are for subjects withhistopathologic diagnoses of carcinoma of the breast. The data includeresults from optional one year mammograms, as well as the requiredbaseline and two year follow-up mammograms. Once a diagnosis of breastcancer was made, these subjects were discontinued from the study andtheir status decoded to reveal the therapy (arm) to which they beenassigned (i.e. what study drug they had received).

[0055] For the studies reported in this invention, the number ofpatients randomly assigned to receive placebo is approximately 3195. Thenumber of patients randomly assigned to receive raloxifene (all dosescombined) is approximately 6681. (In the large, 7704-patient treatmentstudy, the therapy codes have not been revealed for the patients whoremain enrolled in the study. Therefore, the number of patients assignedto each therapy group is an estimation.)

[0056] The results shown below are for patients who were diagnosed tohave breast carcinoma at any time during the study, but at least onemonth after being randomly assigned to study medication (placebo orraloxifene). Table 1 presents the results for all placebo-controlledstudies, with data for all doses of raloxifene pooled. Table 2 presentsa subset of the cases presented in Table 1, specifically the patientsenrolled in the large, 7704-patient treatment study, in which most ofthe cases of breast cancer have occurred. The two raloxifene doses inthis treatment study are 60 mg/day and 120 mg/day. Since the incidenceof breast cancer increases with age, it is expected that the treatmentstudy would have a higher incidence of breast cancer [mean patient ageof 67 years at study entry]. The tables present the number of cases ofbreast cancer (n) for each treatment group, the total number patientsassigned to that treatment (N), an estimate of the relative risk fordeveloping breast cancer, and a 95% confidence interval for the relativerisk of developing breast cancer. Note that if the upper limit of the95% confidence interval is less than 1.0, then there is statisticallysignificant evidence (at the 5% level) that the incidence of breastcancer on raloxifene is less than the incidence of breast cancer onplacebo. TABLE 1 Analysis of Relative Risk of Breast Cancer AllPlacebo-Controlled Studies Combined Time from Therapy Relative 95%Assignment Placebo Raloxifene Risk Confidence to Cases Cases (RaloxifeneInterval for Diagnosis n/N (%) n/N (%) to Placebo) Relative Risk Atleast 24/3195 18/6681 0.36 (0.20, 0.64)  1 month At least 21/319510/6681 0.23 (0.11, 0.45) 12 months

[0057] TABLE 2 Analysis of Relative Risk of Breast Cancer Large(7704-patient) Treatment Study Of Postmenopausal Women with EstablishedOsteoporosis Time from Therapy Relative 95% Assignment PlaceboRaloxifene Risk Confidence to Cases Cases (Raloxifene Interval forDiagnosis n/N (%) n/N (%) to Placebo) Relative Risk At least 21/265912/5317 0.29 (0.15, 0.55)  1 month At least 18/2659  5/5317 0.14 (0.06,0.32) 12 months

[0058] In these placebo-controlled studies, the data clearly indicatethat patients randomly assigned to raloxifene have a decreased incidenceof breast cancer compared with patients randomly assigned to placebo.The estimate of crude relative risk for all patients diagnosed at leastone month after random assignment to study drug is 0.36, with a 95%confidence interval (0.20, 0.64), indicating a 64% decrease in the rateof breast cancer. When the large treatment study is considered alone,the estimate of crude relative risk is 0.29, with 95% confidenceinterval (0.15, 0.55), indicating a 71% decrease in the rate of breastcancer. These results are highly statistically significant.

[0059] Because cancers diagnosed at least 1 year after randomization aremost likely to represent cancers that were not clinically pre-existing,we have also analyzed the data considering only cases which occurred atleast 12 months after randomization to study drug. For allplacebo-controlled studies combined, the crude relative risk estimate is0.23, with a 95% confidence interval (0.11, 0.45), corresponding to a77% decrease in the incidence of breast cancer. For the large treatmentstudy, the estimate of crude relative risk is 0.14, with a 95%confidence interval (0.06, 0.32), corresponding to a 86% decrease in theincidence of breast carcinoma.

[0060] To further analyze the appearance of tumors with respect tolength of time in the study, Tables 3 and 4 present the relative riskdata, which are divided into three time periods: 1) cases diagnosed fromfollow-up of baseline mammograms, i.e., all cases diagnosed between 1and 6 months after study drug assignment; 2) cases diagnosed fromfollow-up of 1-year mammograms, i.e., all cases diagnosed between 6 and18 months after study drug assignment; and 3) cases diagnosed fromfollow-up of 2-year mammograms i.e., all cases diagnosed between 18 and30 months after study drug assignment.

[0061] Table 3 presents the relative risk of breast cancer for each timeperiod for all placebo-controlled studies combined. Table 4 presents theinformation for a subset of patients reported in Table 3, namely, thepatients in the large, 7704-patient treatment study. In both tables, itis evident that the relative risk of developing breast carcinomadecreases with each successive follow-up time period. The relative riskfor both populations achieves statistical significance at the two-yearfollow-up time point. TABLE 3 Annual Relative Risk of Breast Cancer AllPlacebo-Controlled Studies Combined^(a) 95% Confidence PlaceboRaloxifene Relative Interval for Mammograms^(c) Cases Cases RiskRelative Risk Baseline 2 5 1.20 (0.23, 6.15)  (1-6 months)  1-Year  6 70.56 (0.19, 1.63) Follow-up  (6-18 months)  2-year 16 5 0.15 (0.06,0.36) Follow-Up (18-30 months)

[0062] TABLE 4 Annual Relative Risk of Breast Cancer Large(7704-patient) Treatment Study^(a) Of Postmenopausal Women withEstablished Osteoporosis 95% Confidence Placebo Raloxifene RelativeInterval for Mammograms Cases Cases Risk Relative Risk Baseline 2 5 1.25(0.24, 6.42)  (1-6 months)  1-Year  6 4 0.33 (0.10, 1.11) Follow-up (6-18 months)  2-year 13 3 0.12 (0.04, 0.33) Follow-Up (18-30 months)

[0063] As a final summary, FIG. 1 graphically presents the incidence ofbreast cancer in all placebo-controlled studies. (One patient who had abreast carcinoma diagnosed after 30 months is excluded from this graph,so that the graph represents approximately the same follow-up period inboth treatment groups.) The two curves (placebo and raloxifene) arealmost indistinguishable until the 1-year time point, when they becomedivergent, with breast cancer occurrences in the placebo groupincreasing at a greater rate than that seen with raloxifene.

We claim:
 1. A method for preventing breast cancer in a human whichcomprises administering to said human for a sufficient term an effectivedose of a compound of the formula

or a pharmaceutically acceptable salt or solvate thereof.
 2. The methodof claim 1 wherein said effective dose is between about 30 mg to about200 mg/day.
 3. The method of claim 1 wherein said effective dose isbetween about 50 mg to about 150 mg/day.
 4. The method of claim 1wherein said effective dose is between about 60 mg to about 120 mg/day.5. The method of claim 1 wherein said effective dosage is about 60mg/day.
 6. The method of claim 1 wherein said term is at least sixmonths.
 7. The method of claim 1 wherein said term is at least one year.8. The method of claim 1 wherein said term is at least two years.
 9. Themethod of claim 1 wherein said term is chronic.
 10. The method of claim1 wherein said compound is the hydrochloride salt thereof.
 11. Themethod of claim 1 wherein said human is a post-menopausal female, at noparticular risk of developing breast cancer.
 12. The method of claim 1where said breast cancer is de novo.
 13. The method of claim 1 whereinsaid human is a post-menopausal female.
 14. A method for preventingbreast cancer in a post-menopausal human female which comprisesadministering to said post-menopausal human female for a sufficient terman effective dose of a compound of the formula

or a pharmaceutically acceptable salt or solvate thereof.
 15. The methodof claim 14 wherein said effective dose is between about 30 mg to about200 mg/day.
 16. The method of claim 14 wherein said effective dose isbetween about 50 mg to about 150 mg/day.
 17. The method of claim 14wherein said effective dose is between about 60 mg to about 120 mg/day.18. The method of claim 14 wherein said effective dosage is about 60mg/day.
 19. The method of claim 14 wherein said term is at least sixmonths.
 20. The method of claim 14 wherein said term is at least oneyear.
 21. The method of claim 14 wherein said term is at least twoyears.
 22. The method of claim 14 wherein said term is chronic.
 23. Themethod of claim 14 wherein said compound is the hydrochloride saltthereof.
 24. The method of claim 14 wherein said post-menopausal femaleis at no particular risk of developing breast cancer.
 25. The method ofclaim 14 where said breast cancer is de novo.
 26. A method forpreventing breast cancer comprising administrating to a human for asufficient term an effective dose of a compound of formula I

or a pharmaceutically acceptable salt or solvate thereof, said humanbeing at no particular risk of developing breast cancer.
 27. The methodof claim 26 wherein said effective dose is between about 30 mg to about200 mg/day.
 28. The method of claim 26 wherein said effective dose isbetween about 50 mg to about 150 mg/day.
 29. The method of claim 26wherein said effective dose is between about 60 mg to about 120 mg/day.30. The method of claim 26 wherein said effective dosage is about 60mg/day.
 31. The method of claim 26 wherein said term is at least sixmonths.
 32. The method of claim 26 wherein said term is at least oneyear.
 33. The method of claim 26 wherein said term is at least twoyears.
 34. The method of claim 26 wherein said term is chronic.
 35. Themethod of claim 26 wherein said compound is the hydrochloride saltthereof.
 36. The method of claim 26 wherein said human is apost-menopausal female.
 37. An article of manufacture comprisingpackaging material and a pharmaceutical agent contained within saidpackaging material, wherein said packaging material comprises a labelwhich indicates said pharmaceutical agent may be administered, for asufficient term at an effective dose, for preventing breast cancer in ahuman and wherein said pharmaceutical agent is a compound of formula I

or a pharmaceutically acceptable salt or solvate thereof.
 38. An articleof manufacture of claim 36 wherein said label indicates an effectivedose of the compound of formula I is between about 30 mg to about 200mg/day.
 39. An article of manufacture of claim 36 wherein said labelindicates an effective dose of the compound of formula I is betweenabout 50 mg to about 150 mg/day.
 40. An article of manufacture of claim36 wherein said label indicates an effective dose of the compound offormula I is between about 60 mg to about 120 mg/day.
 41. An article ofmanufacture of claim 36 wherein said label indicates an effective dosageof the compound of formula I is about 60 mg/day.
 42. An article ofmanufacture of claim 36 wherein said label indicates the term ofadministration is at least six months.
 43. An article of manufacture ofclaim 36 wherein said label indicates the term of administration is atleast one year.
 44. An article of manufacture of claim 36 wherein saidlabel indicates the term of administration is at least two years.
 45. Anarticle of manufacture of claim 36 wherein said label indicates the termof administration is chronic.
 46. An article of manufacture of claim 36wherein said compound is the hydrochloride salt thereof.
 47. An articleof manufacture of claim 36 wherein said human is a post-menopausalfemale, at no particular risk of developing breast cancer.
 48. Anarticle of manufacture of claim 36 where-said breast cancer is de novo.49. An article of manufacture of claim 36 wherein said human is apost-menopausal female.
 50. An article of manufacture comprisingpackaging material and a pharmaceutical agent contained within saidpackaging material, wherein said packaging material comprises a labelwhich indicates said pharmaceutical agent may be administered, for asufficient term and at an effective dose, for preventing breast cancerin a post-menopausal human female wherein said pharmaceutical agent is acompound of formula I

or a pharmaceutically acceptable salt or solvate thereof.
 51. An articleof manufacture of claim 50 wherein said label indicates an effectivedose of the compound of formula I is between about 30 mg to about 200mg/day.
 52. An article of manufacture of claim 50 wherein said labelindicates an effective dose of the compound of formula I is betweenabout 50 mg to about 150 mg/day.
 53. An article of manufacture of claim50 wherein said label indicates an effective dose of the compound offormula I is between about 60 mg to about 120 mg/day.
 54. An article ofmanufacture of claim 50 wherein said label indicates an effective dosageof the compound of formula I is about 60 mg/day.
 55. An article ofmanufacture of claim 50 wherein said label indicates the term ofadministration is at least six months.
 56. An article of manufacture ofclaim 50 wherein said label indicates the term of administration is atleast one year.
 57. An article of manufacture of claim 50 wherein saidlabel indicates the term of administration is at least two years.
 58. Anarticle of manufacture of claim 50 wherein said label indicates the termof administration is chronic.
 59. An article of manufacture of claim 50wherein said compound is the hydrochloride salt thereof.
 60. An articleof manufacture of claim 50 wherein said post-menopausal female is at noparticular risk of developing breast cancer.
 61. An article ofmanufacture of claim 50 where said breast cancer is de novo.
 62. Anarticle of manufacture comprising packaging material and apharmaceutical agent contained within said packaging material, whereinsaid packaging material comprises a label which indicates saidpharmaceutical agent may be administered, for a sufficient term at aneffective dose, for preventing breast cancer in a human at no particularrisk of developing breast cancer wherein said pharmaceutical agent is acompound of formula I

or a pharmaceutically acceptable salt or solvate thereof.
 63. An articleof manufacture of claim 62 wherein said label indicates the effectivedose of a compound of Formula I is between about 30 mg to about 200mg/day.
 64. An article of manufacture of claim 62 wherein said labelindicates the effective dose of a compound of Formula I is between about50 mg to about 150 mg/day.
 65. An article of manufacture of claim 62wherein said label indicates the effective dose of a compound of FormulaI is between about 60 mg to about 120 mg/day.
 66. An article ofmanufacture of claim 62 wherein said label indicates the effectivedosage of a compound of Formula I is about 60 mg/day.
 67. An article ofmanufacture of claim 62 wherein said label indicates the term is atleast six months.
 68. An article of manufacture of claim 62 wherein saidlabel indicates the term is at least one year.
 69. An article ofmanufacture of claim 62 wherein said label indicates the term is atleast two years.
 70. An article of manufacture of claim 62 wherein saidlabel indicates the term is chronic.
 71. An article of manufacture ofclaim 62 wherein said compound is the hydrochloride salt thereof.
 72. Anarticle of manufacture of claim 62 wherein said human is apost-menopausal female.
 73. The use of a compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for preventing breast cancer in a human,said medicament to be administered to said human for a sufficient termand at an effective dose.
 74. The use of claim 73 wherein said effectivedose is between about 30 mg to about 200 mg/day.
 75. The use of claim 73wherein said effective dose is between about 50 mg to about 150 mg/day.76. The use of claim 73 wherein said effective dose is between about 60mg to about 120 mg/day.
 77. The use of claim 73 wherein said effectivedosage is about 60 mg/day.
 78. The use of claim 73 wherein said term isat least six months.
 79. The use of claim 73 wherein said term is atleast one year.
 80. The use of claim 73 wherein said term is at leasttwo years.
 81. The use of claim 73 wherein said term is chronic.
 82. Theuse of claim 73 wherein said compound is the hydrochloride salt thereof.83. The use of claim 73 wherein said human is a post-menopausal female,at no particular risk of developing breast cancer.
 84. The use of claim73 where said breast cancer is de novo.
 85. The use of claim 73 whereinsaid human is a post-menopausal female.
 86. The use of a compound of theformula

or a pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for preventing breast cancer in apost-menopausal human female, said medicament to be administered to saidpost-menopausal human female for a sufficient term and at an effectivedose.
 87. The use of claim 86 wherein said effective dose is betweenabout 30 mg to about 200 mg/day.
 88. The use of claim 86 wherein saideffective dose is between about 50 mg to about 150 mg/day.
 89. The useof claim 86 wherein said effective dose is between about 60 mg to about120 mg/day.
 90. The use of claim 86 wherein said effective dosage isabout 60 mg/day.
 91. The use of claim 86 wherein said term is at leastsix months.
 92. The use of claim 86 wherein said term is at least oneyear.
 93. The use of claim 86 wherein said term is at least two years.94. The use of claim 86 wherein said term is chronic.
 95. The use ofclaim 86 wherein said compound is the hydrochloride salt thereof. 96.The use of claim 86 wherein said post-menopausal female is at noparticular risk of developing breast cancer.
 97. The use of claim 86where said breast cancer is de novo.
 98. The use of a compound offormula I

or a pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for preventing breast cancer in a humanbeing at no particular risk of developing breast cancer, said medicamentto be administered to said human for a sufficient term and at aneffective dose.
 99. The use of claim 98 wherein said effective dose isbetween about 30 mg to about 200 mg/day.
 100. The use of claim 98wherein said effective dose is between about 50 mg to about 150 mg/day.101. The use of claim 98 wherein said effective dose is between about 60mg to about 120 mg/day.
 102. The use of claim 98 wherein said effectivedosage is about 60 mg/day.
 103. The use of claim 98 wherein said term isat least six months.
 104. The use of claim 98 wherein said term is atleast one year.
 105. The use of claim 98 wherein said term is at leasttwo years.
 106. The use of claim 98 wherein said term is chronic. 107.The use of claim 98 wherein said compound is the hydrochloride saltthereof.
 108. The use of claim 98 wherein said human is apost-menopausal female.
 109. A pharmaceutical formulation comprising asan active ingredient a compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, saidpharmaceutical formulation adapted for preventing breast cancer in ahuman by administration for a sufficient term an effective dose of saidcompound to said human.
 110. The pharmaceutical formulation of claim 109wherein said effective dose is between about 30 mg to about 200 mg/day.111. The pharmaceutical formulation of claim 109 wherein said effectivedose is between about 50 mg to about 150 mg/day.
 112. The pharmaceuticalformulation of claim 109 wherein said effective dose is between about 60mg to about 120 mg/day.
 113. The pharmaceutical formulation of claim 109wherein said effective dosage is about 60 mg/day.
 114. Thepharmaceutical formulation of claim 109 wherein said term is at leastsix months.
 115. The pharmaceutical formulation of claim 109 whereinsaid term is at least one year.
 116. The pharmaceutical formulation ofclaim 109 wherein said term is at least two years.
 117. Thepharmaceutical formulation of claim 109 wherein said term is chronic.118. The pharmaceutical formulation of claim 109 wherein said compoundis the hydrochloride salt thereof.
 119. The pharmaceutical formulationof claim 109 wherein said human is a post-menopausal female, at noparticular risk of developing breast cancer.
 120. The pharmaceuticalformulation of claim 109 where said breast cancer is de novo.
 121. Thepharmaceutical formulation of claim 109 wherein said human is apost-menopausal female.
 122. A pharmaceutical formulation comprising asan active ingredient a compound of the formula

or a pharmaceutically acceptable salt or solvate thereof, saidpharmaceutical formulation adapted for preventing breast cancer in apost-menopausal human female by administration for a sufficient term aneffective dose of said compound to said human.
 123. The pharmaceuticalformulation of claim 122 wherein said effective dose is between about 30mg to about 200 mg/day.
 124. The pharmaceutical formulation of claim 122wherein said effective dose is between about 50 mg to about 150 mg/day.125. The pharmaceutical formulation of claim 122 wherein said effectivedose is between about 60 mg to about 120.mg/day.
 126. The pharmaceuticalformulation of claim 122 wherein said effective dosage is about 60mg/day.
 127. The pharmaceutical formulation of claim 122 wherein saidterm is at least six months.
 128. The pharmaceutical formulation ofclaim 122 wherein said term is at least one year.
 129. Thepharmaceutical formulation of claim 122 wherein said term is at leasttwo years.
 130. The pharmaceutical formulation method of claim 122wherein said term is chronic.
 131. The pharmaceutical formulation ofclaim 122 wherein said compound is the hydrochloride salt thereof. 132.The pharmaceutical formulation of claim 122 wherein said post-menopausalfemale is at no particular risk of developing breast cancer.
 133. Thepharmaceutical formulation of claim 122 where said breast cancer is denovo.
 134. A pharmaceutical formulation comprising as an activeingredient a compound of formula I

or a pharmaceutically acceptable salt or solvate thereof, saidpharmaceutical formulation adapted to prevent breast cancer in a humanbeing at no particular risk of developing breast cancer, byadministration for a sufficient term an effective dose of said compoundto said human.
 135. The pharmaceutical formulation of claim 134 whereinsaid effective dose is between about 30 mg to about 200 mg/day.
 136. Thepharmaceutical formulation of claim 134 wherein said effective dose isbetween about 50 mg to about 150 mg/day.
 137. The pharmaceuticalformulation of claim 134 wherein said effective dose is between about 60mg to about 120 mg/day.
 138. The pharmaceutical formulation of claim 134wherein said effective dosage is about 60 mg/day.
 139. Thepharmaceutical formulation of claim 134 wherein said term is at leastsix months.
 140. The pharmaceutical formulation of claim 134 whereinsaid term is at least one year.
 141. The pharmaceutical formulation ofclaim 134 wherein said term is at least two years.
 142. Thepharmaceutical formulation of claim 134 wherein said term is chronic.143. The pharmaceutical formulation of claim 134 wherein said compoundis the hydrochloride salt thereof.
 144. The pharmaceutical formulationof claim 134 wherein said human is a post-menopausal female.